Inhibition studies of ketol-acid reductoisomerases from pathogenic microorganisms
2020
Wun, Shun Jie | Johnson, Lambro A. | You, Lv | McGeary, Ross P. | Brueck, Thomas | Schenk, Gerhard | Guddat, Luke W.
Ketol-acid reductoisomerase (KARI), the second enzyme in the branched-chain amino acid (BCAA) biosynthesis pathway, is an emerging target for the discovery of biocides. Here, we demonstrate that cyclopropane-1,1-dicarboxylate (CPD) inhibits KARIs from the pathogens Mycobacterium tuberculosis (Mt) and Campylobacter jejuni (Cj) reversibly with Kᵢ values of 3.03 μM and 0.59 μM, respectively. Another reversible inhibitor of both KARIs, Hoe 704, is more potent than CPD with Kᵢ values of 300 nM and 110 nM for MtKARI and CjKARI, respectively. The most potent inhibitor tested here is N-hydroxy-N-isopropyloxamate (IpOHA). It has a Kᵢ of ~26 nM for MtKARI, but binds rather slowly (kₒₙ ~900 M⁻¹s⁻¹). In contrast, IpOHA binds more rapidly (kₒₙ ~7000 M⁻¹s⁻¹) to CjKARI and irreversibly.
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